Cardiac expression of skeletal muscle sodium channels increases longitudinal conduction velocity in the canine 1-week myocardial infarction

Coronel, Ruben; Lau, David H.; Sosunov, Eugene A.; Janse, Michiel J.; Danilo, Peter; Anyukhovsky, Evgeny P.; Wilms-Schopman, Francien J.G.; Opthof, Tobias; Shlapakova, Iryna N.; Ozgen, Nazira; Prestia, Kevin; Kryukova, Yelena; Cohen, Ira S.; Robinson, Richard B.; Rosen, Michael R.

doi:10.1016/j.hrthm.2010.04.009

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Volume 7, Issue 8 , Pages 1104-1110, August 2010

Cardiac expression of skeletal muscle sodium channels increases longitudinal conduction velocity in the canine 1-week myocardial infarction

Ruben Coronel, MD, PhD
- Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, Amsterdam, The Netherlands
- Address reprint requests and correspondence: Ruben Coronel, M.D., Ph.D., Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, K2-112, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
David H. Lau, MD, PhD
- Department of Medicine, Columbia University Medical Center, New York
Eugene A. Sosunov, PhD
- Department of Pharmacology, Columbia University Medical Center, New York
Michiel J. Janse, MD, PhD
- Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, Amsterdam, The Netherlands
Peter Danilo Jr., PhD
- Department of Pharmacology, Columbia University Medical Center, New York
- Center for Molecular Therapeutics, Columbia University Medical Center, New York
Evgeny P. Anyukhovsky, PhD
- Department of Pharmacology, Columbia University Medical Center, New York
Francien J.G. Wilms-Schopman
- Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, Amsterdam, The Netherlands
Tobias Opthof, PhD
- Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, Amsterdam, The Netherlands
Iryna N. Shlapakova, MD
- Department of Pharmacology, Columbia University Medical Center, New York
Nazira Ozgen, MD, PhD
- Department of Pharmacology, Columbia University Medical Center, New York
Kevin Prestia, DVM
- Institute for Comparative Medicine, Columbia University Medical Center, New York
Yelena Kryukova, PhD
- Department of Pharmacology, Columbia University Medical Center, New York
Ira S. Cohen, MD, PhD
- Department of Physiology and Biophysics, Stonybrook University, Stonybrook, New York
Richard B. Robinson, PhD
- Department of Pharmacology, Columbia University Medical Center, New York
- Center for Molecular Therapeutics, Columbia University Medical Center, New York
Michael R. Rosen, MD
- Department of Pharmacology, Columbia University Medical Center, New York
- Center for Molecular Therapeutics, Columbia University Medical Center, New York
- Department of Pediatrics, Columbia University Medical Center, New York, New York

Received 7 December 2009; accepted 2 April 2010. published online 12 April 2010.

Background

Skeletal muscle sodium channel (Nav1.4) expression in border zone myocardium increases action potential upstroke velocity in depolarized isolated tissue. Because resting membrane potential in the 1-week canine infarct is reduced, we hypothesized that conduction velocity (CV) is greater in Nav1.4 dogs compared with in control dogs.

Objective

The purpose of this study was to measure CV in the infarct border zone border in dogs with and without Nav1.4 expression.

Methods

Adenovirus was injected in the infarct border zone in 34 dogs. The adenovirus incorporated the Nav1.4- and a green fluorescent protein (GFP) gene (Nav1.4 group, n = 16) or only GFP (n = 18). After 1 week, upstroke velocity and CV were measured by sequential microelectrode recordings at 4 and 7 mM [K⁺] in superfused epicardial slabs. High-density in vivo epicardial activation mapping was performed in a subgroup (8 Nav1.4, 6 GFP) at three to four locations in the border zone. Microscopy and antibody staining confirmed GFP or Nav1.4 expression.

Results

Infarct sizes were similar between groups (30.6% ± 3% of left ventricle mass, mean ± standard error of the mean). Longitudinal CV was greater in Nav1.4 than in GFP sites (58.5 ± 1.8 vs. 53.3 ± 1.2 cm/s, 20 and 15 sites, respectively; P <.05). Transverse CV was not different between the groups. In tissue slabs, dV/dt_max was higher and CV was greater in Nav1.4 than in control at 7 mM [K⁺] (P <.05). Immunohistochemical Nav1.4 staining was seen at the longitudinal ends of the myocytes.

Conclusion

Nav1.4 channels in myocardium surviving 1 week infarction increases longitudinal but not transverse CV, consistent with the increased dV/dt_max and with the cellular localization of Nav1.4.

Keywords: Conduction, Arrhythmias, Gene therapy, Skeletal muscle, Sodium channel, Myocardial infarction

Abbreviations: CV, Conduction velocity, dV/dt_max, maximum upstroke velocity, GFP, green fluorescent protein, IZ, infarct zone, LV, left ventricle, MDP, maximum diastolic potential, Nav1.4, skeletal sodium channel gene, PBS, phosphate-buffered saline, S1, S2, basic stimulus, premature stimulus, V_L, V_T, longitudinal and transverse conduction velocity